Hepatic fibrosis, and its irreversible form, cirrhosis, afflicts millions of individuals in the US and is a major cause of death for those with chronic liver disease. The long-term objective for the proposed research is the discovery of effective and safe anti-fibrotic agents for treating liver fibrosis and thereby decreasing the risk of cirrhosis in individuals with liver disease. Activation and trans-differentiation of the hepatic stellate cell (HSC) into the collagen-forming myofibroblast are key events involved in liver fibrosis. We, and others, have shown that stimulation of adenosine receptors on other matrix forming cells leads to inhibition of activation, proliferation, and synthesis of connective tissue proteins. We propose that inhibition/ reversal of HSC activation in fibrosis can be achieved through stimulation of adenosine receptors on HSCs. The research plan includes the use of various subtype specific adenosine receptor agonists, antagonists, and agents that modulate adenosine metabolism and biosynthesis. Using these biological tools and other molecular probes, all available at Metabasis Therapeutics, rat HSCs will be studied in order to confirm the presence of adenosine receptors and probe their function. After identification of the subtype, the concept will be tested using an in-vivo model of fibrosis. PROPOSED COMMERCIAL APPLICATIONS: Given the worldwide increase in liver disease resulting in hepatic fibrosis/ cirrhosis, and the current lack of proven therapies, the medical need and potential market for a therapeutic to treat hepatic fibrosis are large. The research in this proposal will provide the scientific and commercial foundation to support the development of a novel small- molecule therapeutic for the treatment of hepatic fibrosis/cirrhosis.